Novel use of taurolin

ABSTRACT

Taurolin compounds are used as blood coagulation-inhibiting agents and as abacterial inflammation-inhibiting agents. The outstanding coagulation-inhibiting action of taurolin is especially suitable for use in medical conditions requiring dialysis and for vascular protheses. These compounds can also be used together with other anti-coagulants such as coumarin or heparin.

DESCRIPTION

It is known to counter a blood embolus formation (thrombosis) to acertain extent by administration of coagulation-inhibiting medicaments.Coagulation-inhibiting medicaments (anticoagulants) in the narrowersense delay or prevent the blood coagulation; to these medicamentsbelong heparin and the coumarins, such as e.g. Marcumar®(3-(1-phenylpropyl)-4-hydroxycoumarin). In addition, there are alsoknown so-called coagulation-inhibiting medicaments in the wider sensewhich are certain fibrinolytic and thrombolytic (i.e. fibrin- and bloodembolus-dissolving) materials, such as e.g. streptokinase and urokinase,and inhibiting materials of the thrombocyte aggregation or of theprostaglandin synthesis, such as e.g. acetylsalicylic acid.

Taurolin is used in medicine as a good bactericidally-active substance.Taurolin has a low solubility in water (about 1%). Because of its verygood bactericidal and other properties (no resistance against thissubstance known; apart from individually occurring slight local tissueirritation, other undesired side effects are not known), solutions oftaurolin are used for bone lavage for the combating and treatment ofbacterial osteolitis and bacterial suppurative peritonitis. Besides thevery good bactericidal effectiveness, for taurolin is also known aninhibiting action on the formation of adhesions of the peritoneum afteroperative intervention into the abdominal cavity, as well as thesuitability of taurolin for the neutralization of the endotoxin in thecase of the so-called endotoxin shock; further medicinal fields of usehave hitherto not been known for taurolin (cf. e.g. C. Steinbach-Lebbinet.al., Arzneimittelforschung/Drug Research 32 (II), No. 12 (1982),1542-1546; W. Siegenthaler, Klinische Pathophysiologie, Georg ThiemeVerlag, Stuttgart 1976).

It has now been found that, besides its known good bactericidal action,taurolin surprisingly also displays a coagulation-inhibiting action.Therefore, the subject of the present invention is the use of taurolinas blood coagulation-inhibiting agent, especially for the extracorporealcirculation, for example for plasmaphoresis, dialysis, blood lavage,oxygenators and for protheses in the vascular system.

The action according to the invention is surprising and also in"Taurolin", published by W. L. Bruckner and R. W. Pfirrmann, VerlagUrban und Schwarzenberg, Munchen 1985, it is expressly stated thattaurolin does not influence the blood coagulation and displays noanti-phlogistic action.

Since the coagulation-inhibiting action of taurolin occurs not only invivo but also in vitro, taurolin can, as mentioned, also be used for thecoagulation inhibition in the extracorporeal circulation (e.g. in thecase of heart operations or in the case of haemodialysis in theartificial kidney). The use of taurolin is thereby above all indicatedin those cases in which the formation or entrainment of blood emboli inthe vascular system (e.g. thrombosis, embolism) is to be prevented, thusin the first place in the case of heart infarct and in the case of veinthrombosis with the danger of a lung embolism, but also in the case ofthreatening blockage of blood vessels, in the case of blood vesseldiseases and after injuries or operations for the prevention of thepost-traumatic thromboses.

An undesired side effect of the known anti-coagulants, such as heparinor the coumarin derivatives, results, above all, from their desiredcoagulation-inhibiting and therefore, inter alia, blood flow-promotingactions. It can thereby, above all, result in hemorrhages in thegastro-intestinal tract (e.g. in the case of the so-called "quiet"gastric ulcer, in brain hemorrhages and in hemorrhages in the drainingoff urinary tract or in would hemorrhages during and after operationsand after injuries. For the avoidance of such undesired phenomena, itis, therefore, important to monitor the remaining coagulatability of theblood during the administration by means of various coagulation tests,e.g. by the so-called "Quick test". In the case of an overdosing,hitherto the too strong action in the case of the coumarin derivativesmust be reduced by high doses of coagulation factors and possibly alsoof vitamin K and the too strong action of heparin must be removed e.g.by neutralization with protamine.

It has now been ascertained that in the case of the use according to theinvention of taurolin as coagulation-inhibiting agent, thesedisadvantages do not occur but, on the contrary, a sufficient bloodcoagulatability is always still maintained and, therefore, even in thecase of an inadvertent false dosaging, the danger does not exist that acomplete suppression of the blood coagulation takes place and thusdangerous hemorrhages could occur. Thus, e.g. it was found in vitro thatin the case of the addition of taurolin to blood plasma (5 ml. of pooledplasma of various persons was mixed with increasing amounts up to max.50 mg. taurolin, whereby the maximum dosage, i.e. thus 50 mg./5 ml.,corresponds to a 1% solution, which simultaneously also corresponds tothe solubility limit of taurolin), a corresponding reduction of theQuick value and an also corresponding prolongation of the PTT occurs andthe blood coagulation is not completely suppressed as is the case e.g.under the same conditions in the case of the use of heparin. Therefore,in comparison with known anti-coagulants, the use of taurolin has theadvantage that a sufficient blood coagulatability always still remainsand, therefore, an overdosing is not possible.

In the case of vascular protheses, hitherto the thrombus formation onthe surface was prevented either by binding of coagulation-inhibitingheparin in the inner walls of the protheses or recently increasingly bycoating with physical plasmas. However, the action of these measures hasbeen found to be very brief. For the long-term maintenance of thefunction of a vascular prothesis, one now aims for the formation of aso-called neointima on the inner walls of protheses. For the formationof a neointima, the synthetic resin surfaces of the lumen of thevascular prothesis (e.g. Dacron or Teflon) must woven velours-like andbrought into contact with blood components; this best takes place beforethe implantation. After the implantation, there then takes place adeposition of white blood cells on the so pretreated surfaces. After acomparatively long contact with the blood, there was obtained theformation of a substantially complete endothelial layer on the velourssurface. This artificially produced endothelial layer, which is calledneointima, can prevent the undesired thrombi formation on the surface ofthe prothesis. However, this process possesses the disadvantage that itis very time-consuming and laborious. Furthermore, it is therebynecessary, up to the formation of a dependable neointima, additionallyto administer systemic anti-coagulants for months and years, whichinvolves the known risks.

In the case of the use of taurolin according to the invention ascoagulation inhibitor, this disadvantage can be avoided, i.e. thetime-consuming and laborious process for the prevention of the thrombiformation on the prothesis surface can thereby be overcome in a simpleway in that one treats the surface with taurolin and then exposesdirectly to the blood stream. In this way, the result which oneotherwise achieves by formation of the neointima is achieved practicallyimmediately. Alternatively, one can also introduce the taurolin directlyinto the blood stream. This embodimental form is also unquestionablebecause the tauroli, in the case of the maximum possible dosaging in theblood, lowers the Quick value to a maximum of 20% and does not increasethe PTT value above 60 seconds. These data correspond to the therapeuticvalues aimed for in the case of the treatment of heart infarct patientswith Marcumar®. This means that thus also in the case of the treatmentof the heart infarct, the previously known anti-coagulants, such as e.g.Marcumar® and heparin, can be replaced by taurolin, whereby, inaddition, one can also avoid the disadvantages involved with thepreviously known anti-coagulants, such as especially the danger ofhemorrhages.

The dosaging and manner of application of taurolin depends upon thefield of use and the therapeutic aim in general according to theguidelines known for the known anti-coagulants, such as e.g. Marcumar®and heparin, whereby the most suitable values for the particularindividual case, modes of administration and measures are easy todetermine by orientating tests, such as e.g. the measurement of thereduction of the Quick value. As taurolin, in the scope of the inventionare understood compounds of the general formula ##STR1## wherein R¹signifies a hydrogen with 1 to 6 carbon atoms and R² a hydrogen atom, analkyl radical with 1 to 6 carbon atoms or a radical according to thegeneral formula ##STR2## wherein R¹ possesses the given meanings.

4,4'-Methylene-bis-(tetrahydro-2H-1,2,4-thiadiazine-1,1-dioxide) ispreferred. A similar coagulation-inhibiting action, in part in weakenedform, can also be shown by the compounds standing in equilibrium in anaqueous solution of taurolin (e.g. 2H-1,2,4-thiadiazine-1,1-dioxide andespecially its 4-hydroxymethyl derivative and the ring fission productsstanding in equilibrium in the case of heating, such as e.g.1-hydroxymethylamino-2-sulphamoylethane and 1-amino-2-sulphamoylethane),as well as the taurolin metabolites (cf. C. Steinbach-Lebbin et.al.,Arzneimittelforschung/ 5 Drug Research 32 (II), No. 12 (1982)1542-1546). Therefore, above and in the following, by taurolin is alsoto be understood these decomposition products and metabolites.

As dialysis materials and vascular protheses, there can be used allmaterials hitherto known and described in the literature (cf. e.g.Artificial Organs, Vol. 5 (Suppl.) 1981 507; Trans. Am. Soc. Artif.Intern. Organs, Vol. XXV (1979) 280; Vol. XXVII (1981) 396, 499, 511 and648; Vol. XXVIII (1982) 459 and 478; Vol. XXIX (1983) 200).

The administration can, as a rule, take place in the usual manner foranti-coagulants, thus e.g. intravenously, intraperitoneally, perorallyor as infusion. In comparison with heparin, the taurolin used accordingto the invention further possesses the advantage that it maintains theaction, with equally rapid commencement, long and uniformly and taurolincan also be administered orally; the use previously necessary in manycases (e.g. in the treatment of a heart infarct) of the combination ofan initial heparin injection and subsequent oral administration of acoumarin derivative, the action of which admittedly commences delayedbut can be administered in oral form, is thereby not necessary. Asolution of taurolin in water is preferably used.

For the use according to the invention as coagulation-inhibiting agent,the taurolin can be administered as sole component or also together withother components. The form of administration (pharmaceuticalcomposition) can contain conventional additive materials, such asconventional pharmaceutical confectioning and/or dilution agents, andpossibly also further active materials insofar as these show noundesired side effects with the other components and are suitable forthe assistance of the therapy; in particular, in some cases it can alsobe expedient to use the taurolin together with known anti-coagulants,such as e.g. heparin and/or coumarin derivatives, such as Marcumar®,e.g. simultaneously (in the same form of administration) or also oneafter the other. A reduction of the dose of the known anti-coagulantsand thus of their known risks in use is hereby also possible.

It has also been found that the single contact with taurolin with anartificial surface, such as e.g. of a synthetic resin or metal surface,continuously effectively prevents the deposition of blood coagula on theartificial surface in vivo, i.e. after an implantation or a temporaryintroduction of an object of the synthetic material into an organismthrough which blood flows. Therefore, this coagulation action can servefor the use of the taurolin for the treatment of surfaces of medicalapparatus which are temporarily introduced into the blood stream, suchas e.g. vein catheters (which, untreated, tend to blockage due to bloodcoagula which again represents a breeding place for bacteria, wherebythe danger of a sepsis is brought about). The treatment of the apparatuscan be carried out e.g. with an aqueous taurolin solution, especially a1% aqueous taurolin solution. By means of an intermittent rinsing ofvascular catheters, it is, in this way e.g. possible to prevent thecoagula formation on the catheter tips.

The manner of action of taurolin on the blood coagulation system differsfundamentally from that of the previously known coagulation-inhibitingagents. Coumarin derivatives act by reduction of the rate cf synthesisof coagulation factors--as vitamin K antagonists; therefore, theiraction takes place delayed, i.e. in dependence upon the half life timeof the coagulation factors which amount to between 20 and 100 hours.Heparin acts by activation of antithrombin III which, in turn, functionsas inhibitor of the serine proteases of the coagulation system;furthermore, it is bound to the cell surfaces of the cells on the wallsof the blood vessels--the endothelial cells--and to various co-factorsof the coagulation. In contradistinction thereto, taurolin inhibitsdependent upon concentration and thereby readily controlably thefunction of antithrombin III. Taurolin can thereby also be used asantidote (counter-agent) in the case of heparin over-dosings with theadvantage that, after the use of taurolin, due to the taurolin acoagulation-inhibiting action still remains.

On the basis of its surprising novel coagulation-inhibiting action,there furthermore also comes into question the use of taurolin asantidote (counter-agent) when the coagulation system has been activatedby other blood coagulation-effective substances, such as e.g. snakevenom (cf. e.g. "Methods in Enzymology, Vol. XLV, "Proteolytic Enzymes",Part B, 1976, Academic Press, New York/San Francisco/London).

How the coagulation-inhibiting action of the taurolin comes about couldnot yet be fully elucidated. However, a marked direct action of thetaurolin on the Factor XII of the coagulation system was ascertained;this is of especial interest because the activated Factor XII bringsabout the activation of the kallikrein/kinine system, of thefibrinolysis system and of the complement system. Since inflammatoryreactions of the vascular connective tissue are brought about especiallyvia the kallikrein/kinine system but also via the complement system, thetaurolin has, therefore, also an inflammation-inhibiting action. Fromthis result the following medicinal uses (indications) for taurolin:non-bacterial inflammations of the bones, of the cartilage and of thesoft parts, e.g. arthritis, arthroses, rheumatoid diseases in thechronic and acute stage; inflammations of glandular organs and of thegastro-intestinal tract, e.g. the non-bacterial inflammation ofglandular organs; allergic inflammations, e.g. toxic nephritis; chronicinflammations which can form around implanted foreign materials withoutthe co-action of bacteria. Thus, taurolin can be used e.g. for theslowing down or suppression of the foreign body reaction of theorganism. For this purpose, the active material taurolin can beintroduced e.g. into the interior of the foreign material in order then,after implantation, to emerge into the organism or into the surroundingtissue and there manifest its intended action.

Therefore, the subject of the present invention is also the use oftaurolin as inflammation-inhibiting agent, especially in the scope ofthe above-mentioned indications.

The following Examples explain the invention in more detail withoutlimiting it thereto.

EXAMPLE 1

Foils of cellulose acetate were treated with a 15 aqueous solution oftaurolin (period of action 30 minutes at 37° C.) and subsequentlybrought into contact with fresh blood (period of action 30 minutes at37° C.). After removal of the blood and rinsing off of the foil surfacewith physiological common salt solution, no fibrin fibre deposition onthe surface could be ascertained by electron raster photographs, whereasone was ascertained in the case of surfaces not pretreated with taurolinsolution but otherwise the same.

A cellulose acetate foil which was first brought into contact with ataurolin/blood plasma mixture (taurolin 1% dissolved in the plasma)subsequently also showed no blood coagulation or fibrin deposition onthe wall when it is thereafter rinsed with physiological common saltsolution and then incubated with fresh blood from healthy donors for 30minutes at 37° C.

It was also found that, quite generally, the surface of syntheticmaterials which are implanted in an organism become thromboresistant bycontact with taurolin and maintains this effect when the taurolin hasalready been removed from the surface. From this it is recognized thatthe contact according to the invention of taurolin with an artificialsurface effectively continuously prevents the deposition of bloodcoagula on the artificial surface in vivo, i.e. after implantation ofthe device of synthetic material in an organism with blood flow-through.

EXAMPLE 2

Samples of, in each case, 5 ml. of a pooled plasma of variousexperimental persons were mixed with increasing amounts of taurolin,namely, with amounts of 0 (1), 10 (2), 20 (3), 30 (4), 40 (5) and 50 (6)mg. of taurolin/5 ml. plasma (the figures given in brackets give thesample numbers).

The Quick test and the PTT test was carried out for the samples 1 to 6and the following results (30 minutes) obtained (Table 1):

    ______________________________________                                                  sample No.                                                                    1    2       3      4     5    6                                    ______________________________________                                        Quick test (%)                                                                            92     65      53   44    39   35                                 PTT (in sec.)                                                                             34.1   38.0    43.0 48.8  55.9 61.8                               ______________________________________                                    

Furthermore, in the case of samples 1 to 6, for the various coagulationfactors (plasma factors), there was determined the reduction of thevalues by the taurolin addition (according to the methods of factoranalysis as are stated by the manufacturers of corresponding testsystems, e.g. of Behringwerke AG, Marburg or American Hospital SupplyDeutschland GmbH, Munchen).

The results obtained are summarized in Table 2:

                                      TABLE 2                                     __________________________________________________________________________           coagulation factor                                                     sample No.                                                                           II  V    VII                                                                              X   IX  XI   XII VIII                                      __________________________________________________________________________    1      108%                                                                              164% 94%                                                                              82% 321%                                                                              312% 185%                                                                              121%                                      2      96% 121% 79%                                                                              75% 153%                                                                              301% 177%                                                                              48%                                       3      87% 110% 74%                                                                              65% 81% 197% 77% 21%                                       4      90%  92% 74%                                                                              56% 63% 140% 64% 13%                                       5      75%  81% 77%                                                                              53% 65%  83% 55%  6%                                       6      74%  79% 73%                                                                              50% 68%  47% 61%  6%                                       __________________________________________________________________________

The values in Table 2 show clearly that all investigated blood factorsare reduced by taurolin (initial value is the absolute value in percentgiven for the untreated sample No. 1) but that in no case does areduction to 0% take place.

The results contained in Example 2 show that, under the conditionsemployed, the blood coagulation is not completely suppressed by thetaurolin, whereas this is the case, e.g. in the case of replacement oftaurolin by heparin under otherwise the same conditions. From this canbe seen that the use of taurolin according to the invention, in the caseof its use as coagulation inhibitor, is less questionable than thepreviously known coagulation inhibitors because, due to the incompletesuppression of the blood coagulation even in the case of unintendedfalse dosaging (over-dosaging), the danger does not exist of thecomplete suppression of the blood coagulation and thus of a hemorrhage.

I claim:
 1. A composition in a pharmaceutically effective amount forpreventing blood coagulation comprisinga taurolin compound of theformula ##STR3## wherein R¹ is H or a C₁ -C₆ alkyl and R² is H, a C₁ -C₆alkyl or a group of the formula: ##STR4## wherein R¹ is H or a C₁ -C₆alkyl, and heparin or an anti-coagulant coumarin derivative consistingof 3-(1-phenylpropyl)-4-hydroxycoumarin wherein the compounds arepresent in an amount effective to lower the Quick value to a maximum of20% and wherein the PTT value does not increase above 60 seconds in apatient.
 2. A reagent for preventing blood coagulation comprisingapharmaceutically effective amount of at least one taurolin compound ofthe formula ##STR5## wherein R¹ is H or a C₁ -C₆ alkyl, R² is H, C₁ -C₆alkyl or a group of the formula ##STR6## wherein R¹ is H or a C₁ -C₆alkyl, and heparin or a coumarin derivative consisting of3-(1-phenylpropyl)-4-hydroxycoumarin wherein the compounds are presentin an amount effective to lower the Quick value to a maximum of 20% andwherein the PTT value does not increase above 60 sec. in a patient.
 3. Amethod of inhibiting blood coagulation in or near prosthetic deviceafter said device has been inserted in a patient which comprisesadministering a taurolin compound to the prosthetic device in apharmaceutically effective amount sufficient to inhibit bloodcoagulation in or about said device after insertion f placement in or onthe patient in need of the device and wherein the taurolin compound isof the formula: ##STR7## wherein R¹ is H or a 1-6 carbon alkyl group andR² is H, a 1-6 carbon alkyl group or a group of the general formula:##STR8## wherein R¹ is H or a 1-6 carbon alkyl group.
 4. Method of claim3 comprising administering said taurolin compound to the propheticdevice by administration into a patient's extracorporeal circulation. 5.Method of claim 3 comprising administering said taurolin compound to aprosthetic device consisting of a vascular prothesis inserted in saidafflicted subject.
 6. Method of claim 3 wherein said subject isafflicted with at least one condition selected from the group consistingof myocardial infarct, vein thrombosis, blood vessel blockage, bloodvessel diseases and after injuries or operation for the prevention ofpost-traumatic thrombosis.
 7. A method according to claim 3 wherein saidtaurolin compound is4,4'-methylene-bs-(tetrahydro-2H,1,2,4-thiadiazine-1,1-doxide).
 8. Amethod for inhibiting blood coagulation in or near a prosthetic devicewherein said device is inserted into the extracorporeal circulation of apatient which comprisesadministering a taurolin compound to theprosthetic device in a pharmaceutically effective amount sufficient toinhibit blood coagulation in or about said device together with or afterinsertion or placement into the extracorporeal circulation of thepatient and wherein the taurolin compound is of the formula ##STR9##wherein R¹ is H or a 1-6 carbon alkyl group and R² is H, a 1-6 carbonalkyl group or a group of the general formula: ##STR10## wherein R¹ is Hor a 1-6 carbon alkyl group.
 9. A method for inhibiting coagulation ofblood caused by vascular prosthesis or extracorporeal devices in apatient which comprises:treating the surface of the prosthesis or devicewith an effective blood coagulation inhibiting amount of a taurolincompound of the formula ##STR11## wherein R¹ is H or a 1-6 carbon alkylgroup and R² is H, a 1-6 carbon alkyl group or a group of the generalformula: ##STR12## wherein R¹ is H or a 1-6 carbon alkyl group.
 10. Themethod of claim 9 further comprising administering said taurolingcompound to the blood circulation in an amount effective to inhibitblood coagulation.
 11. Method of any one of claim 3, 8 or 9 furthercomprising inhibiting blood coagulation by administering the taurolincompound together with another anti-coagulant comprising a coumarinderivative consisting of 3-(1-phenylpropyl-4-hydroxycoumarin or heparinwherein the anti-coagulant compounds are present in a pharmaceuticallyeffective amount.
 12. Method for preventing blood coagulation in the useof vascular catheter and prosthesis in a patient whichcomprises:administering to the circulation a pharmaceutically effectiveamount of a taurolin compound selected from the group consisting of4-4-Methylene-bos-(tetrahydro 2-H-1,2,4-thiadiazine-1,1-dioxide,1-hydroxymethylamino-2-sulphamoylethane, 1-amino-2-sulphamoylethane or a4-hydroxymethyl derivative thereof, and 2H-1,2,4-thiadiazine-1,1-dioxideor a 4-hydroxymethyl derivative thereof to inhibit blood coagulation.13. Method for inhibiting blood coagulation in the use of vascularprostheses in a patient which comprises:administering to the circulationa pharmaceutically effective amount of a taurolin compound4-4'-Methylene-bis-(tetrahydro-2H-1,2,3-thiadiazine-1,1-dioxide) toinhibit blood coagulation.
 14. A method for inhibiting blood coagulationin a patient having a medical condition requiring bloodcoagulation-inhibition which comprises administering to the circulationof a patient in need of said blood coagulation-inhibition treatment upto a 1% solution of a taurolin compound selected from the groupconsisting of4-4-Methylene-bis-(tetrahydro-2H-1,2,4-thiadiazine-1-amino-2-sulphamyl-ethane,2H-1,2,4-thiadiazine-1,1-dioxide and a 4-hydroxymethyl derivative of2H-1,2,4-thiadiazine-1,1-dioxide to inhibit blood coagulation. 15.Method for combating an overdoes of a blood-coagulation active agentcomprising administering to a patient in need thereof an effectiveamount o a taurolin compound of the formula: ##STR13## wherein R¹ is Hor a C₁ -C₆ alkyl and R² is H a C₁ -C₆ alkyl or a group of the formula##STR14## wherein R¹ is H or a C₁ -C₆ alkyl.